Non-typhoidal Salmonella serotypes (NTS) are a leading cause of food-borne infections worldwide, with S. Typhimurium and S. Enteritidis being isolated most frequently. In immunocompetent individuals, NTS cause a localized gastroenteritis with low mortality rates. However, NTS cause bacteremia in patients with acquired immunodeficiency syndrome (AIDS). The high prevalence of HIV in sub-Saharan Africa has made NTS a leading cause of bacteremia in this region, resulting in considerable mortality (21 to 38%). AIDS patients acquiring an infection with NTS usually present with bacteremia while gastroenteritis is not observed. There is currently no information available on how human immunodeficiency virus (HIV) and NTS synergize to cause this atypical clinical picture. Our long-range goal is to understand the pathogenesis of infections with NTS in HIV patients. The objectives of this application are to investigate mechanisms resulting in a synergy between these pathogens during co- infection using animal and tissue culture models. Our central hypothesis is that SIV causes a depletion of TH17 cells in the gut, thereby promoting a cytokine imbalance during NTS infection that results in defects in epithelial barrier function. We plan to test our hypothesis and fulfill the objectives of this application by pursuing the following specific aim: 1) Determine the contribution of TH17 cytokines to epithelial responses. 2) Determine how SIV-mediated cytokine imbalance effects epithelial barrier function. The rationale for the proposed research is that a better understanding of the mechanisms by which HIV impairs innate immune response to NTS infection will be relevant for the treatment or prevention of other opportunistic infections at mucosal surfaces. We are particularly well prepared to perform the proposed studies as we have assembled a team of well-prepared investigators with access to state-of-the-art facilities at the California National Primate Research Center. PUBLIC HEALTH RELEVANCE Salmonella causes bacteremia in patients with acquired immunodeficiency syndrome (AIDS), resulting in considerable mortality, particularly in Sub-Saharan Africa. There is currently no information available on how human immunodeficiency virus (HIV) and Salmonella synergize during co-infection. The objectives of this application are to use a simian immunodeficiency virus (SIV)/NTS Rhesus macaque model to determine how the innate immune response to Salmonella is altered in HIV patients.